Smooth muscle has been implicated to play a role in a large number of diseases affecting the urinary tract (e.g. urinary incontinence), the digestive system (e.g. irritable bowel syndrome), the circulatory system and the reproductive system. Large conductance potassium ion channels (BK channels), also called Maxi-K or slo1, are membrane associated ion channels, which conduct potassium ions across a cell membrane. BK channels are present in a wide variety of tissues throughout the body, and are activated (opened) or deactivated (closed) by two physiologically relevant factors; a change in intracellular calcium ion (Ca2+) concentration, or a change in the electrical potential across the cell membrane. An increase in the activity of BK channels leads to a decrease in cell excitability and a concurrent hyperpolarization of the cell membrane. As such, BK channels are critical in the regulation of smooth muscle tone, neuronal excitability, secretion, contractility to name a few.
Drugs that activate or open BK channels are in high demand for their potential clinical use. Primary indications for BK channel openers include urinary incontinence, irritable bowel syndrome, diabetes and arterial hypertension, cardiovascular diseases including myocardial infarction, erectile dysfunction, airway constriction and preterm labour caused by overactive uterine contractions.
Only one BK opener, Andolast (CR 2039, N-4-(5-tetrazolyl)-phenyl-4-(5-tetrazolyl)-benzamide) is currently in development, in phase 3 clinical trials in bronchial pneumonia patients in a comparison study with inhaled corticosteroids. Three other BK openers have failed in clinical development and have been discontinued. This class of drugs is however of exceptional importance and commercial value and has been of interest as a target for drug discovery, because experimental evidence suggests BK Channels play a pivotal and specific role in many pathophysiological conditions. This class of drug will elicit smooth muscle relaxation. As a result, in diseases such as urinary incontinence, where a hallmark of the disease or condition is overactive spastic smooth muscle, a BK channel opener will relax the spastic muscle, returning it to normal functioning and decreasing the urge that accompanies urinary incontinence.
The current market leader for the treatment of urinary incontinence is Detrol® (marketed by Pfizer), and all other drugs on the market used to treat this condition are of the same classification; muscarinic antagonists. Detrol® and similar muscarinic antagonists bind to, but do not activate muscarinic cholinergic receptors. Rather they act by blocking the action of endogenous acetylcholine, a neurotransmitter found in both peripheral and central nervous systems. These agents have widespread effects including actions on the iris and ciliary muscles in the eye and on organs such as the heart and vasculature, secretions associated with the respiratory tract, the GI system, salivary glands, and the CNS—contributing to a plethora of side effects from the drugs. The most common side effects from muscarinic antagonists like Detrol® include blurred vision, constipation, dizziness, drowsiness, dry eyes, dry mouth, headache, indigestion, stomach pain. More severe side effects can include severe allergic reactions such as a rash, hives, itching, difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, or tongue, unusual hoarseness, chest pain, confusion, difficult or painful urination, disorientation, fast or irregular heart beat, hallucinations, memory problems, severe dizziness, swelling of the hands, ankles or feet.
Approximately one in 6 people in the USA are affected by overactive bladder. The condition is the result of bladder muscle contraction and squeezing too often, causing frequent and strong urges to urinate, in addition to undesired wetting incidences affecting sleep, social life, health and well-being, relationships and feelings of self-worth.